Method of manufacturing optically active (-)-2-halo-1-(substituted phenyl) ethanol by ketone reduction

ABSTRACT

A method is proposed for manufacturing (-)-2-bromo-1-(3&#39;-chlorophenyl) ethanol by bringing a 2-bromo-1-(3&#39;-chlorophenyl) ethanone into contact with a microorganism belonging to 9 genuses including Ashbya genus and Brettanomycess genus to thereby reduce it asymmetrically into (-)-2-bromo-1-(3&#39;-chlorophenyl) ethanol, and for manufacturing (-)-substituted styrene oxide by cyclizing the obtained alcohol under alkaline conditions. The (-)-substituted styrene oxide can be manufactured efficiently.

FIELD OF THE INVENTION

The present invention relates to a method of manufacturing (-)-2-halo-1-(substituted phenyl) ethanol and (-)-substituted styrene oxide and more particularly to a method of efficiently manufacturing (-)-2-halo-1-(substituted phenyl) ethanol by bringing a microorganism into contact with 2-halo-1-(substituted phenyl) ethanone and to a method of manufacturing (-)-substituted styrene oxide efficiently through cyclization thereof under alkaline conditions.

These compounds are useful as materials for synthesis of drugs, agrichemicals et cetera requiring to be optically active.

BACKGROUND OF THE INVENTION

As to optically active (-)-2-halo-1-(substituted phenyl) ethanol, the present inventors have not yet seen any patent, report or the like relating to its manufacture. Meanwhile, as to optically active chloro-substituted styrene oxide, there is a report that 72-86% e.e. could be achieved by epoxidation of chloro-substituted styrene by means of Nocardia corallina (Keizo Furuhasi; Organic Synthetic Chemistry, 43, 162 (1987)). Another known method of synthesis thereof is by interphase moving reaction between chloro-substituted benzaldehyde and dimethyl sulfonium methylide, but this method is extremely poor in optical purity attainable (Hiroyuki Sawada; Japanese Laid-open Patent Publication No. 105024/1976.

After having made intensive studies for development of an efficient method of manufacturing optically active (-)-2-halo-1-(substituted phenyl) ethanol and (-)-substituted styrene oxide, the present inventors discovered existence of some microorganisms capable of asymmetrically reducing 2-halo-1-(substituted phenyl) ethanone stereospecifically and converting it into (-)-2-halo-1-(substituted phenyl) ethanol and thus completed the invention.

DISCLOSURE OF THE INVENTION

The first aspect of the present invention is to provide a method of bringing a 2-halo-1-(substituted phenyl) ethanone represented by a general formula [1] ##STR1## (where X represents a chlorine atom or a bromine atom and each of substitution groups R¹, R² and R³ represents a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group or a methoxy group except cases where 3 substitution groups are all hydrogen atoms) into contact with a microorganism selected from those belonging to Ashbya genus, Brettanomyces genus, Candida genus, Cryptococcus genus, Geortrichum genus, Pichia genus, Rhodosporidium genus, Rhodotorula genus, Saccharomyces genus, Torulopsis genus or Trigonopsis genus capable of reducing it asymmetrically into (-)-2-halo-1-(substituted phenyl) ethanol represented by a general formula [[2] ##STR2## (where X and substitution groups R¹, R² and R³ are the same as in the general formula [1] and * indicates an asymmetric carbon atom) and thereby to prepare (-)-2-halo-1-(substituted phenyl) ethanol.

The second aspect of the invention is to provide a method of manufacturing (-)-substituted styrene oxide represented by a general formula [3] ##STR3## (where substitution groups R¹, R² and R³ are the same as in the general formula [1] and [2] and * indicates an asymmetric carbon atom) by cyclizing under alkaline conditions (-)-2-halo-1-(substation phenyl) ethanol represented by the general formula [2] ##STR4## (where X and substitution groups R¹, R² and R³ are the same as in the general formula [1] and * indicates an asymmetrical carbon atom).

OPTIMUM MODE OF EMBODYING THE INVENTION

The microorganism used in the present invention for asymmetrical reduction of 2-halo-1-(substituted phenyl) ethanone for conversion into (-)-2-halo-1-(substituted phenyl) ethanol can be found in the following way.

For example, 50 ml of A culture medium comprising 40 g of glucose, 3 g of yeast extract, 13 g of (NH₄)₂ HPO₄, 7 g of KH₂ PO₄, 0.8 g of MgSO₄ 7H₂ O, 60 mg of ZnSO₄ 7H₂ O, 90 mg of FeSO₄ 7H₂ O, 5 mg of CuSO₄ 5H₂ O, 10 mg of MnSO₄.4H₂ O and 0.1 g of NaCl (per liter) is put into a 500 ml Sakaguchi flask, a given microorganism is inoculated after sterilization and the culture medium is cultured under shaking for 2 days at 30° C. Thereafter, cells are is collected by centrifugal separation, is suspended in 25 ml of 0.1M phosphate buffer solution (pH 7.0) containing 0.5% of 2-bromo-1-(3'-chlorophenyl) ethanone and 3% of glucose and shaken in a 500 ml Sakaguchi flask for 2-3 days at 30° C. It is then admixed with an equivalent amount of ethyl acetate, this followed by extraction, and the resulting (-)-2-bromo-1-(3'-chlorophenyl) ethanol is analyzed by gas chromatography (column: silicone OV-7, φ0.3×200 cm, column temperature 190° C., N₂ gas pressure 1.2 kg/cm²). The optical purity of (-)-2-bromo-1-(3'-chlorophenyl) ethanol can be determined by high-performance liquid chromatography (column: Nippon Bunko K. K.'s Chiralcel-OJ, dissolving solvent:hexane/isopropanol (50/1), flow rate: 1.0 ml/min., detection: 220 nm) after refining the extracted oil by distillation with the oil separated in 44.8 minutes of retention time for (-) isomer and 54.9 minutes of retention time for (+) isomer.

As microorganism may be used any of the known genuses capable of asymmetrical reduction of 2-halo-1-(substituted phenyl) ethanone for conversion into (-)-2-halo-1-(substituted phenyl) ethanol.

As such may be exemplified, among others, Ashbya gossypii IFO 0560, Brettanomyces custersianus IFO 1585, Candida humicola CBS 2774, Candida intermedia IFO 0761, Candida krusei IFO 0011, Candida magnoliae IFO 0705, Candida pinus IFO 0741, Candida saitoana IFO 0768, Candida sake CBS 2219, now available as IFO 1021 Candida tropicalis IFO 1403, Cryptococcus albidus IFO 0378, Cryptococcus terreus IFO 0727, Trichosporon CBS 7065, IFO 0574, Pichia membranaefaciens IFO 0460, Rhodosporidium toruloides IFO 0871, Rhodotorula glutinis IFO 1099, Rhodotorula glutinis var. dairenesis IFO 0415, Rhodotorula graminis IFO 0190, Rhodotorula minuta IFO 0387, Rhodotorula rubra IFO 0383, Saccharomyces cerevisiae IFO 0614 and Trigonopsis variabilis IFO 0671.

For the cultivation of these microorganisms may be used usually any nutriment which they can assimilate. For the cultivation thereof, therefore, may be used an ordinary culture media containing proper amounts of, for example, carbohydrates such as glucose and sucrose, alcohols such as ethanol and glycerol, hydrocarbons such as paraffin, organic acids such as acetic acid and propionic acids, carbon sources such as soy bean oil and mixtures thereof, yeast extracts, peptone, meat extracts, corn steep liquor, nitrogen-containing inorganic and organic nutriments such as ammonium sulfate and ammonia; inorganic nutriments such as phosphates, magnesium, iron, manganese and potassium, and vitamins such as biotin and thiamine. Cultivation is carried out aerobically for 1-5 days at 20°-40° C. with pH of the nutrient medium adjusted to 4.0-9.5.

As reducing method are known, for instance, a method in which a culture solution is used as it is and a method in which cells are separated by centrifugal separation and resuspended in, for example, a phosphate buffer solution or water and then it is admixed with 2-halo-1-(substituted phenyl) ethanone for reaction to proceed. For the reaction a carbon source such as glucose or sucrose may be added to the culture medium as an energy source. The cells may be used as live cells but may as well be used after acetone treatment or freeze drying. Such cells may also be used with them fixed on a carrier. 2-halo-1-(substituted phenyl) ethanone may be added as it is or after dissolution in an organic solvent lest it should interfere with the progress of the reaction either en bloc at the start of the reaction or in portions as the reaction proceeds. The reaction may be conducted under stirring for 3-120 hours at a temperature of 10°-60° C. with proper pH adjustment in a range of 5-9.

Separation of (-)-2-halo-1-(substituted phenyl) ethanol as the reaction product may be done directly from the reaction liquor or after separation of cells followed by extraction by the use of a solvent such as ethyl acetate and dichlormethane, dehydration and subsequent refining by distillation or silica gel chromatography, and in this way (-)-2-halo-1-(substituted phenyl) ethanol of a high purity can be obtained with ease. Its optical purity can be determined in the same way as described above by high-performance liquid chromatography by the use of column, Chiral cel-OJ and hexane/isopropanol (30-50/l) as eluate.

The (-)-2-halo-1-(substituted phenyl) ethanol thus obtained can be easily cyclized by heating or leaving at the room temperature under coexistence of an alkali such as NaOH in a quantity of not less than the equivalent mol and can be converted into (-)-substituted styrene oxide.

Hereinafter the present invention will be described in greater detail with reference to preferred examples but it is to be understood that the present invention is by no means limited thereby.

Unless otherwise noted, [%] in the following description means [weight %].

EXAMPLE 1

50 ml of the aforementioned A culture medium was put into a 500 ml Sakaguchi flask and after sterilization the microorganisms shown in Table 1 were inoculated thereon, and aerobical cultivation was carried out under shaking for 2 days at 30° C. Cells were taken from the culture solution by centrifugal separation, 0.5% of 2-bromo-1-(3'-chlorophenyl) ethanone was suspended in 25 ml of 0.1M phosphate buffer solution (pH 7.0) containing 0.3% glucose and reaction was carried out under shaking in the 500 ml Sakaguchi flask for 48 hours at 30° C. After completion of the reaction, (-)-2-bromo-1-(3'-chlorophenyl) ethanol was extracted twice using the equivalent amount of ethyl acetate and the resulting ethyl acetate layer was analyzed by gas chromatography for determination of the degree of conversion. Then, after dehydration of ethyl acetate with Glauber's salt anhydride, the solvent was removed and (-)-2-bromo-1-(3'-chlorophenyl) ethanol was obtained. This was dissolved in methylene chloride and its optical purity was determined by high-performance liquid chromatography. The results were as shown in Table 1.

                  TABLE 1                                                          ______________________________________                                                            (-)-2-bromo-1-(3'-                                                             chlorophenyl) ethanol                                                                  Optical                                                                Yield (%)                                                                              purity (%)                                          ______________________________________                                         Ashbya gossypii IFO 0560                                                                            55        72                                              Brettanomyces custersianus IFO 1585                                                                 10        100                                             Candida humicola CBS 2774                                                                           40        90                                              Candida intermedia IFO 0761                                                                         54        100                                             Candida krusei IFO 0011                                                                             31        100                                             Candida magnoliae IFO 0705                                                                          80        81                                              Candida pinus IFO 0741                                                                              44        92                                              Cryptococcus albidus IFO 0378                                                                       59        92                                              Cryptococcus terreus IFO 0727                                                                       63        98                                              Pichia farinosa IFO 0574                                                                            44        81                                              Pichia membranaefaciens IFO 0460                                                                    21        100                                             Rhodosporidium toruloides IFO 0871                                                                  79        100                                             Rhodotorula glutinis IFO 1099                                                                       56        67                                              Rhodotorula glutinis var.                                                                           75        100                                             dairenensis IFO 0415                                                           Rhodotorula graminis IFO 0190                                                                       51        100                                             Rhodotorula minuta IFO 0387                                                                         8         99                                              Rhodotorula rubra IFO 0383                                                                          56        100                                             Saccharomyces cerevisiae IFO 0614                                                                   21        76                                              Trigonopsis variabilis IFO 0671                                                                     76        88                                              ______________________________________                                    

EXAMPLE 2

Rhodotorula glutinis var. direnensis IFO 0415 was inoculated on 3 liters of A culture medium in a 5-liter minijar fermentator and cultivated for 24 hours under stirring (500 rpm.) at 30° C. with air being introduced at a rate of 1 vvm. After completion of cultivation, cells were collected by centrifugal separation and 7.5 g of 2-bromo-1-(3'-chlorophenyl) ethanone and 38 g of glucose were added and reaction was carried out for 24 hours at 30° C. under stirring (150 rpm.) with pH being adjusted to 7.0 by the use of NaOH. After the completion of the reaction, the reaction product was extracted twice using 750 ml of ethyl acetate. The ethyl acetate layer was first dehydrated using Glauber's salt anhydride, then the solvent was removed under reduced pressure and thus 5.2 g of an oily substance was obtained. This was distilled (130° C./3 mmHg) and there was obtained 3.9 g of colorless, oily (-)-2-bromo-1-(3'-chlorophenyl) ethanol. Its specific rotation [α]_(D) ²⁰ was -25.5° (c=1.02 CH₃ OH) and its optical purit y was 100% e.e. as it was determined by high-performance liquid chromatography.

H-NMR (90 MHz, CDCl₃) δ ppm 2.88 (br. S, 1H), 3.35-3.90 (m, 4H), 4.90 (d.d, J=315, 8 Hz, 1H) 6.98-7.51 (m, 4H)

EXAMPLE 3

Bio-reaction and analysis were carried out in the same way as described in Example 1 except that the microorganisms used were those shown in Table 2 and as substrate was used 2-bromo-1-(2'-chlorophenyl) ethanone instead of 2-bromo-1-(3'-chlorophenyl) ethanone and as the reaction product (-)-2-bromo-1-(2'-chlorophenyl) ethanol was obtained. The results were as shown in Table 2.

                  TABLE 2                                                          ______________________________________                                                            (-)-2-bromo-1-(2'-chloro-                                                      phenyl) ethanol                                                                            Optical                                         Microorganisms       Yield (%) purity (%)                                      ______________________________________                                         Candida humicola CBS 2774                                                                           23        92                                              Candida intermedia IFO 0761                                                                         23        92                                              Candida krusei IFO 0011                                                                             5         100                                             Candida magnoliae IFO 0705                                                                          98        96                                              Candida pinus IFO 0741                                                                              32        96                                              Candida saitoana IFO 0768                                                                           13        91                                              Candida sake IFO 1021                                                                               31        96                                              Candida tropicalis IFO 1403                                                                         32        86                                              Cryptococcus albidus IFO 0378                                                                       15        98                                              Cryptococcus terreus IFO 0727                                                                       39        100                                             Trichosporon oubioeri CBS 7065                                                                      27        92                                              Pichia farinosa IFO 0574                                                                            34        88                                              Rhodosporidium toruloides IFO 0871                                                                  62        98                                              Rhodotorula glutinis IFO 1099                                                                       87        100                                             Rhodotorula glutinis ver.                                                                           15        100                                             dairenensis IFO 0415                                                           Rhodotorula graminis IFO 0190                                                                       31        98                                              Rhodotorula rubra IFO 0383                                                                          17        100                                             Trigonopsis variabilis IFO 0671                                                                     7         99                                              ______________________________________                                    

EXAMPLE 4

Bio-reaction and analysis were conducted in the same way as described in Example 2 except that as microorganism was used Rhodotorula glutinis IFO 1099 and as substrate was used 2-bromo-1-(2'-chlorophenyl) ethanone and as the reaction product was obtained 4.2 g of (-)-2-bromo-1-(2'-chlorophenyl) ethanol.

Its specific rotation [α]_(D) ²⁰ was 41.5° (C=1.02, CH₃ OH) and its optical purity as determined by high-performance liquid chromatography was 100% e.e.

H-NMR (90 MHz, CDCl₃) δ ppm 2.78-3.06 (m, 1H), 3.39 (d.d, J=9, 10 Hz, 1H), 3.73 (d.d, J=2.5, 10 Hz, 1H), 5.04-5.39 (m, 1H), 6.68-7.68 (m, 4H)

EXAMPLE 5

Bio-reaction and analysis were carried out in the same way as described in Example 2 except that as microorganisms were used those shown in Table 3 and as substrate was used 2-bromo-1-(4'-chlorophenyl) ethanone instead of 2-bromo-1-(3'-chlorophenyl) ethanone and as the reaction product (-)-2-bromo-1-(4'-chlorophenyl) ethanol was obtained. The results were as shown in Table 3.

                  TABLE 3                                                          ______________________________________                                                            (-)-2-bromo-1-(4'-chloro-                                                      phenyl) ethanol                                                                            Optical                                         Microorganisms       Yield (%) purity (%)                                      ______________________________________                                         Ashbya gossypii IFO 0560                                                                            47         95                                             Burettanopmyces custersianus IFO 1585                                                               11         100                                            Candida humicola CBS 2774                                                                           51         73                                             Candida intermedia IFO 0761                                                                         26         72                                             Candida krusei IFO 0011                                                                             8          87                                             Candida magnoliae IFO 0705                                                                          89         68                                             Candida pinus IFO 0741                                                                              25         96                                             Candida saitoana IFO 0768                                                                           55         98                                             Candida tropicalis IFO 1403                                                                         21         90                                             Cryptococcus alibidus IFO 0378                                                                      24         97                                             Cryptococcus terreus IFO 0727                                                                       9          100                                            Pichia falinosa IFO 0574                                                                            51         84                                             Rhodosporidium toruloides IFO 0871                                                                  17         88                                             Rhodotorula glutinis IFO 1099                                                                       55         93                                             Rhodotorula glutinis var.                                                                           67         100                                            direnensis IFO 0415                                                            Rhodotorula graminis IFO 0190                                                                       31         89                                             Rhodotorula rubra IFO 0383                                                                          18         94                                             Trigonopsis variabilis IFO 0671                                                                     42         76                                             ______________________________________                                    

EXAMPLE 6

Bio-reaction and analysis were carried out in the same way as described in Example 2 except that as substrate was used 2-bromo-1-(4'-chlorophenyl) ethanone instead of 2-bromo-1-(3'-chlorophenyl) ethanone and as the reaction product was obtained 3.6 g of (-)-2-bromo-1-(4'-chlorophenyl) ethanol.

Its boiling point was 115°-120° C./4 mmHg, specific rotation [α]_(D) ²⁰ was 26.6° (C=1.10, CH₃ OH) and its optical purity as determined by high-performance chromatography was 100% e.e.

H-NMR (90 MHz, CDCl₃) δ ppm 2.77 (br, S, 1H), 3.18-3.70 (m, 2H), 4.82 (d.d, J=3.5, 7.5 Hz, 1H), 6.82-7.44 (m, 4H)

EXAMPLE 7

Bio-reaction and analysis were carried out in the same way as described in Example 2 except that as substrate was used 3.25 g each of 2-bromo-1-(2'-chlorophenyl) ethanone, 2-chloro-1-(3'-chlorophenyl) ethanone and 2-chloro-1-(4'-chlorophenyl) ethanone instead of 2-bromo-1-(3'-chlorophenyl) ethanone and as the reaction products (-)-2-chloro-1-(2'-chlorophenyl) ethanol, (-)-2-chloro-1-(3'-chlorophenyl) ethanol and (-)-2-chloro-1-(4'-chlorophenyl) ethanol were obtained respectively. The yields and physical properties of the respective reaction products were as shown in Table 4.

                                      TABLE 4                                      __________________________________________________________________________     Substrate 2-chloro-1-                                                                              2-chloro-1-                                                                              2-chloro-1-                                                (2'-chloro-                                                                              (3'-chloro-                                                                              (4'-chloro-                                                phenyl)ethanone                                                                          phenyl)ethanone                                                                          phenyl)ethanone                                  Reaction  (-)-2-chloro-1-                                                                          (-)-2-chloro-1-                                                                          (-)-2-chloro-1-                                  product   (2'-chlorophenyl)                                                                        (3'-chlorophenyl)                                                                        (4'-chlorophenyl)                                          ethanol   ethanol   ethanol                                          Yield     1.7 g     1.4 g     1.3 g                                            Boil. point                                                                              150° C./5 mmHg                                                                    130° C./3-4 mmHg                                                                  140° C./5 mmHg                            Specific  -55.6°                                                                            -33.8°                                                                            -36.1°                                    rotation                                                                       [α].sub.D.sup.20                                                         (C = 1, CH.sub.3 OH)                                                           Optical   100%      100%      100%                                             purity                                                                         H-NMR     3.29(brs, S, 1H)                                                                         2.69(br, S, 1H)                                                                          2.27(br, S, 1H)                                  (90 MHz   3.50(dd, J=11.5,                                                                         3.27-3.90(m, 2H)                                                                         3.41-3.82(m, 2H)                                 CDCl.sub.3)                                                                              8.5Hz, 1H)                                                           δ ppm                                                                              3.85(dd, J=11.5,                                                                         4.88(dd, J=3.5,                                                                          4.83(dd, J=4.5,                                            3Hz, 1H)  8Hz, 1H)  7.5Hz, 1H)                                                 5.30(dd, J=11.5,                                                                         7.15-7.54(m, 4H)                                                                         7.11-7.50(m, 4H)                                           3Hz, 1H)                                                                       7.07-7.75(m, 4H)                                                     __________________________________________________________________________

EXAMPLE 8

10 g each of (-)-2-halo-1-(chloro-substituted phenyl) ethanols obtained in Examples 2, 4, 6 and 7 was admixed with 5 ml of 40% NaOH aqueous solution and 10 ml of methylene chloride and was caused to react for 6 hours at 50° C. After cooling, the reaction product was admixed with 20 ml of methylene chloride, the methylene chloride layer was washed with saturated brine and after dehydration and filtration, methylene chloride was removed under reduced pressure and an oily epoxide was thus obtained. This was refined by distillation under reduced pressure and each (-)-chloro-substituted styrene oxide was obtained as shown in Table 5.

                                      TABLE 5                                      __________________________________________________________________________              (-)-2-bromo-                                                                           (-)-2-chloro                                                                           (-)-2-bromo-                                                                            (-)-2-bromo-                                          1-(3'-chloro                                                                           1-(3'-chloro                                                                           1-(2'-chloro                                                                            1-(4'-chloro                                          phenyl)ethanol                                                                         phenyl)ethanol                                                                         phenyl)ethanol                                                                          phenyl)ethanol                               __________________________________________________________________________     (-)-chloro-                                                                             (-)-3'-chloro-  (-)-2'-chloro                                                                           (-)-4'-chloro                                substituted                                                                             styrene oxide   styrene oxide                                                                           styrene oxide                                styrene oxide                                                                  Yield    6.2 g   7.1 g   5.4 g    5.7 g                                        Boil. point                                                                             90-93° C./                                                                      90-93° C./                                                                      80-85° C./                                                                       85-90° C./                                     5 mmHg  5 mmHg  4 mmHg   4 mmHg                                       [α].sub.D.sup.20                                                                  -11.8°                                                                          -11.8°                                                                          -67.5°                                                                           -25.5°                                (C = 1, CHCl.sub.3)                                                            H-NMR    2.75(dd, J=2.5, 6Hz, 1H)                                                                       2.63(dd, J=2.5                                                                          2.75(dd, 1H)                                 (90 MHz  3.13(dd, J=3.5, 6Hz, 1H)                                                                       6Hz, 1H) 3.08(dd, 1H)                                 CDCl.sub.3)                                                                             3.84(dd, J=2.5, 3.5Hz, 1H)                                                                     3.15(dd, J=3,                                                                           3.77(dd, 1H)                                 δ ppm                                                                             7.10-7.45(m, 4H)                                                                               6Hz, 1H) 6.99-7.42(m,                                                          4.17(dd, J=2.5                                                                          14H)                                                                  4Hz, 1H)                                                                       7.01-7.51(m, 4H)                                      __________________________________________________________________________

EXAMPLE 9

500 ml of the aforementioned A culture medium was put into a 2-liter Sakaguchi flask, Rhodotorula glutinis IFO 0415 was inoculated thereon, cultivation was done in the same way as described in Example 1, the resulting cells were collected, 1.5 g of 2-chloro-(4'-fluorophenyl) ethanone was suspended in 300 ml of 0.1M phosphate buffer solution (pH 7.0) containing 0.3% glucose, the suspension was put into the 2-liter Sakaguchi flask and it was reacted under shaking for 48 hours at 30° C. After the reaction was over, the reaction product was extracted twice using 300 ml of ethyl acetate. After dehydration of the ethyl acetate layer with Glauber's salt anhydride, the solvent was removed under reduced pressure and thus an oily substance was obtained. It was then distilled (105° C./4 mmHg) and 1.3 g of (-)-2-chloro-1-(4'-fluorophenyl) ethanol was obtained as a colorless oily substance. Its specific rotation [α].sub. D²⁰ was 38.81° (c=1,01 CH₃ OH) and its optical purity was 100% e.e. as it was determined by means of high-performance liquid chromatography.

1 g of this (-)-2-chloro-1-(4'-fluorophenyl) ethanol was then admixed with the equivalent mol of 40% aqueous solution of NaOH and 5 ml of methylene chloride and the mixture was caused to react for 6 hours at 50° C. After cooling, 5 ml of methylene chloride was added, the methylene chloride layer was washed with saturated brine and after dehydration and filtration, methylene chloride was removed under reduced pressure and crude epoxide was obtained as an oily substance. This was refined under reduced pressure (85° C., 4 mmHg) and 0.65 g of (-)-4'-fluorostyrene oxide was obtained in a colorless oily form. Its specific rotation [α]_(D) ²⁰ was -20.96° (c=1.04 CHCl₃).

(-)-2-chloro-1-(4'-chlorophenyl) ethanol

H-NMR(90 MHz, CDCl₃) δ ppm 3.00 (S, 1H), 3.40-3.83 (m, 2H), 4.85 (d.d, J=4.5, 7.5 Hz, 1H) 6.83-7.53 (m, 4H)

(-)-4'-fluorostyrene oxide

H-NMR (90 MHz, CDCl3) δ ppm 2.72 (d.d, J=2.5, 6.0 Hz, 1H), 3.08 (d.d, J=4.5, 6.0 Hz, 1H), 3.82 (d.d. J=2.5, 4.0 Hz, 1H), 6.85-7.45 (m, 4H)

EXAMPLE 10

Cultivation, reaction and purification were carried out in the same way as described in Example 9 except that 2-chloro-1-(2', 4'-dichlorophenyl) ethanon, 2-chloro-1-(3', 4'-dichlorophenyl) ethanone, 2-chloro-1-(2', 5'-dichlorophenyl) ethanone were used as substrate, and (-)-2-chloro-1-(2', 4'-dichlorophenyl) ethanol, (-)-2-chloro-1-(3', 4'-dichlorophenyl) ethanol, (-)-2-chloro-1-(2', 5'-dichlorophenyl) ethanol was obtained. The yield, specific rotation and optical purity determined by high-performance liquid chromatography were shown in Table 6.

Then, epoxidated in the same way as Example 9, (-)-2', 4'-dichlorostyrene oxide, (-)-3', 4'-dichlorostyrene oxide, (-)-2', 5'-dichlorostyrene oxide were obtained. The yield and the specific rotation were as shown in Table 6.

                                      TABLE 6                                      __________________________________________________________________________     Substrate 2-chloro-1-                                                                              2-chloro-1-                                                                              2-chloro-1-                                                (2',4'-dichloro                                                                          (3',4'-dichloro                                                                          (2',5'-dichloro                                            phenyl)ethanone                                                                          phenyl)ethanone                                                                          phenyl)ethanone                                  Reaction  (-)-2-chloro-1-                                                                          (-)-2-chloro-1-                                                                          (-)-2-chloro-1-                                  product   (2',4'-dichloro-                                                                         (3',4'-dichloro-                                                                         (2',5'-dichloro-                                           phenyl)ethanol                                                                           phenyl)ethanol                                                                           phenyl)ethanol                                   Yield     0.7 g     0.8 g     0.85 g                                           Form      Colorless oil                                                                            Colorless oil                                                                            Colorless oil                                    Boil. point                                                                              160° C./4 mmHg                                                                    170° C./4 mmHg                                                                    140° C./4 mmHg                            Specific  -51.37°                                                                           -32.72°                                                                           -43.40°                                   rotation                                                                       [α].sub.D.sup.20                                                         (C = 1, CH.sub.3 OH)                                                           Optical   100% e.e. 100% e.e. 100% e.e.                                        purity                                                                         H-NMR     2.86(br, S, 1H)                                                                          2.95(br, S, 1H)                                                                          2.98(br, S, 1H)                                  (90 MHz   3.46-3.88(m, 2H)                                                                         3.48(dd, J=8.5                                                                           3.48(dd, J=9.0                                   CDCl.sub.3)                                                                              4.96(dd, J=4.5,                                                                          11.5Hz, 1H)                                                                              12.0Hz, 1H)                                      δ ppm                                                                              7.0Hz, 1H)                                                                               3.85(dd, J=3.0,                                                                          3.85(dd, J=3.0,                                            7.13-7.70(m, 4H)                                                                         11.4Hz, 1H)                                                                              11.0Hz, 1H)                                                          5.18(dd, J=3.0,                                                                          5.25(dd, J=3,0,                                                      8.5Hz, 1H)                                                                               8.5Hz, 1H)                                                           7.18-7.65(m, 3H)                                                                         7.35-7.59(m, 2H)                                 Reaction  (-)-2',4'-di-                                                                            (-)-3',4'-di-                                                                            (-)-2',5'-di-                                    product   chloro styrene                                                                           chloro styrene                                                                           chloro styrene                                             oxide     oxide     oxide                                            Yield     0.61 g    0.65 g    0.68 g                                           Form      Colorless oil                                                                            Colorless oil                                                                            Colorless oil                                    Boil. point                                                                              120° C./4 mmHg                                                                    125° C./4 mmHg                                                                    110° C./4 mmHg                            Specific  -61.30°                                                                           -18.30°                                                                           -22.15°                                   rotation                                                                       [α].sub.D.sup.20                                                         (C = 1, CH.sub.3 OH)                                                           H-NMR     2.61(dd, J=2.5,                                                                          2.73(dd, J=2.5,                                                                          2.66(dd, J=3.0,                                  (90 MHz   5.5Hz, 1H)                                                                               5.5Hz, 1H)                                                                               6.0Hz, 1H)                                       CDCl.sub.3)                                                                              3.17(dd, J=3.0,                                                                          3.12(dd, J=4.0,                                                                          3.21(dd, J=5.5,                                  δ ppm                                                                              5.5Hz, 1H)                                                                               5.5Hz, 1H)                                                                               4.5Hz, 1H)                                                 4.12(dd, J=2.5,                                                                          3.80(dd, J=2.5,                                                                          4.17(dd, J=3.0,                                            3.5Hz, 1H)                                                                               4.0Hz, 1H)                                                                               4.5Hz, 1H)                                                 7.05-7.41(m, 3H)                                                                         7.02-7.05(m, 3H)                                                                         7.16-7.46(m, 3H)                                 __________________________________________________________________________      N

EXAMPLE 11

Cultivation and reaction were carried out in the same way as described in Example 9 except that 2-chloro-1-(2',3',4'-trichlorophenyl) ethane was used as substrate and, after the reaction was over, extraction was done twice using 300 ml ethyl acetate. The ethyl acetate layer was dehydrated with Glauber's salt anhydride, this followed by removal of solvent under reduced pressure, and an oily substance was obtained. It was then refined by silica gel chromatography (hexane/ethyl acetate=7/1) and 1.1 g of a colorless oil of (-)-2-chloro-1-(2',3',4'-trichlorophenyl) ethanol was obtained. Its specific rotation [α]_(D) ²⁰ was -52.29° (C=1.07 CH₃ OH) and its optical purity was 100% e.e. as it was determined by high-performance liquid chromatography.

(-)-2'-chloro-1-(2',3',4'-trichlorophenyl) ethanol

H-NMR(90 MHz, CDCl3) δ ppm 3.10(br,S,1H), 3.50(d.d, J=9.0, 11.0 Hz,1H) 3.85(d.d,J=3.0, 11.0 Hz,1H) 5.25(d.d,J=3.0, 8.5 Hz,1H) 7.35-7.59(m,2H)

EXAMPLE 12

Cultivation, reaction and purification were carried out in the same way as described in Example 9 except that 2-chloro-1-(2'-methylphenyl) ethanone, 2-chloro-1-(3'-methylphenyl) ethanone, 2-chloro-1-(4'-methylphenyl) ethanone were used as substrate, and (-)-2-chloro-1-(2'-methylphenyl) ethanol, (-)-2-chloro-1-(3'-methylphenyl) ethanol, (-)-2-chloro-1-(4'-methylphenyl) ethanol were obtained. The yield, specific rotation and optical purity determined by high-performance liquid chromatography were shown in Table 6.

Then, the reaction product was epoxidated in the same way as Example 9, and (-)-2'-methylstyrene oxide, (-)-3'-methylstyrene oxide, (-)-4'-methylstyrene oxide were obtained. The yield and the specific rotation were as shown in Table 7.

                                      TABLE 7                                      __________________________________________________________________________     Substrate 2-chloro-1-                                                                              2-chloro-1-                                                                              2-chloro-1-                                                (2'-methyl-                                                                              (3'-methyl                                                                               (4'-methyl                                                 phenyl)ethanone                                                                          phenyl)ethanone                                                                          phenyl)ethanone                                  Reaction  (-)-2-chloro-1-                                                                          (-)-2-chloro-1-                                                                          (-)-2-chloro-1-                                  product   (2'-methyl-                                                                              (3'-methyl-                                                                              (4'-methyl-                                                phenyl)ethanol                                                                           phenyl)ethanol                                                                           phenyl)ethanol                                   Yield     1.3 g     1.2 g     1.3 g                                            Form      Colorless oil                                                                            Colorless oil                                                                            Colorless oil                                    Boil. point                                                                              110° C./4 mmHg                                                                    115° C./4 mmHg                                                                    120° C./4 mmHg                            Specific  -56.96°                                                                           -40.39°                                                                           -42.58°                                   rotation                                                                       [α].sub.D.sup.20                                                         (C = 1, CH.sub.3 OH)                                                           Optical   100% e.e. 100% e.e. 100% e.e.                                        purity                                                                         H-NMR     2.30(br, 3H)                                                                             2.35(S, 3H)                                                                              2.35(S, 3H)                                      (90 MHz   2.72(br, S, 1H)                                                                          2.60(br, S, 1H)                                                                          2.68(br, S, 1H)                                  CDCl.sub.3)                                                                              3.37-3.77(m, 2H)                                                                         3.46-3.85(m, 2H)                                                                         3.46-3.85(m, 2H)                                 δ ppm                                                                              5.03(dd, J=4.5,                                                                          4.82(dd, J=5.0                                                                           4.85(dd, J=5.0                                             8.5Hz, 1H)                                                                               7.5Hz, 1H)                                                                               7.5Hz, 1H)                                                 7.01-7.61(m, 3H)                                                                         7.03-7.42(m, 4H)                                                                         7.00-7.40(m, 4H)                                 Reaction  (-)-2'-methyl-                                                                           (-)-3'-methyl-                                                                           (-)-4'-methyl-                                   product   styrene oxide                                                                            styrene oxide                                                                            styrene oxide                                    Yield     0.8 g     0.8 g     0.8 g                                            Form      Colorless oil                                                                            Colorless oil                                                                            Colorless oil                                    Boil. point                                                                              70° C./4 mmHg                                                                     75° C./4 mmHg                                                                     80°  C./4 mmHg                            Specific  -80.59°                                                                           -23.01°                                                                           -29.46°                                   rotation                                                                       [α].sub.D.sup.20                                                         (C = 1, CH.sub.3 OH)                                                           H-NMR     2.39(br, 3H)                                                                             2.30(S, 3H)                                                                              2.30(S, 3H)                                      CDCl.sub.3)                                                                              2.63(dd, J=2.5,                                                                          2.69(dd, J=2.5,                                                                          2.73(dd, J=2.5,                                  δ ppm                                                                              6.0Hz, 1H)                                                                               6.0Hz, 1H)                                                                               5.5Hz, 1H)                                                 3.09(dd, J=3.0,                                                                          3.03(dd, J=3.0,                                                                          3.03(dd, J=4.5,                                            5.5Hz, 1H)                                                                               6.0Hz, 1H)                                                                               5.5Hz, 1H)                                                 3.93(dd, J=2.5,                                                                          3.74(dd, J=2.5,                                                                          3.74(dd, J=2.5,                                            3.0Hz, 1H)                                                                               3.0Hz, 1H)                                                                               4.5Hz, 1H)                                                 7.15(S, 4H)                                                                              6.89-7.29(m, 4H)                                                                         7.12(S, 4H)                                      __________________________________________________________________________

EXAMPLE 13

Cultivation, reaction and purification were carried out in the same way as described in Example 9 except that 2-chloro-1-(2',4'-dimethylphenyl) ethanone and 2-chloro-1-(3',4'-dimethylphenyl) ethanone were used as substrate, and (-)-2-chloro-1-(2',4'-dimethylphenyl) ethanol and (-)-2-chloro-1-(3',4'-dichlorophenyl) ethanol were obtained. The yield, specific rotation and optical purity determined by high-performance liquid chromatography were shown in Table 8.

Then, epoxidated in the same way as Example 9, (-)-2',4'-dimethylstyrene oxide and (-)-3',4'-dimethylstyrene oxide were obtained. The yield and the specific rotation were as shown in Table 8.

                                      TABLE 8                                      __________________________________________________________________________     Substrate 2-chloro-1-(2',4'-                                                                           2-chloro-1-(3',4'-                                               dimethylphenyl)ethanone                                                                      dimethylphenyl)ethanone                                Reaction  (-)-2-chloro-1-(2',4'-                                                                       (-)-2-chloro-1-(3',4'-                                 product   dimethylphenyl)ethanol                                                                       dimethylphenyl)ethanol                                 Yield     1.3 g         1.3 g                                                  Form      Colorless oil Crystal (mp. 61.5° C.)                          Boil. point                                                                              130° C./4 mmHg                                                                        125° C./4 mmHg                                  Specific  -39.80°                                                                               -49.37°                                         rotation                                                                       [α].sub.D.sup.20                                                         (C = 1, CH.sub.3 OH)                                                           Optical   100% e.e.     100% e.e.                                              purity                                                                         H-NMR     2.31(S, 6H)   2.28(S, 6H)                                            (90 MHz   2.59(br, S, 1H)                                                                              2.55(br, S, 1H)                                        CDCl.sub.3)                                                                              3.45-3.85(m, 2H)                                                                             3.60-3.80(m, 2H)                                       δ ppm                                                                              5.08(dd, J=4.0, 9.0Hz, 1H)                                                                   4.85(dd, J=4.5, 7.5Hz, 1H)                                       6.90-7.56(m, 3H)                                                                             7.00-7.31(m, 3H)                                       Reaction  (-)-2',4'-dimethyl-                                                                          (-)-3',4'-dimethyl-                                    product   styrene oxide styrene oxide                                          Yield     0.76 g        0.73 g                                                 Form      Colorless oil Colorless oil                                          Boil. point                                                                              90° C./4 mmHg                                                                         88° C./4 mmHg                                   Specific  -69.14°                                                                               -29.03°                                         rotation                                                                       [α].sub.D.sup.20                                                         (C = 1, CH.sub.3 OH)                                                           H-NMR     2.28(S, 3H)   2.22(S, 6H)                                            (90 MHz   2.35(S, 3H)   2.73(dd, J=2.5, 5.5Hz, 1H)                             CDCl.sub.3)                                                                              2.65(dd, J=3.0, 6.0Hz, 1H)                                                                   3.05(dd, J=4.0, 5.5Hz, 1H)                             δ ppm                                                                              3.08(dd, J=3.0, 6.0Hz, 1H)                                                                   3.75(dd, J=2.5, 4.0Hz, 1H)                                       3.98(dd, J=3.0, 4.0Hz, 1H)                                                                   6.88-7.27(m, 3H)                                                 6.83-7.26(m, 3H)                                                     __________________________________________________________________________

EXAMPLE 14

Cultivation, reaction and purification were carried out in the same way as described in Example 9 except that 2-chloro-1-(2'-methoxyphenyl) ethanone, 2-chloro-1-(3'-methoxyphenyl) ethanone, 2-chloro-1-(4'-methoxyphenyl) ethanone were used as substrate and (-)-2-chloro-1-(2'-methoxyphenyl) ethanol, (-)-2-chloro-1-(3'-methoxyphenyl) ethanol and (-)-2'-chloro-1-(4'-methoxyphenyl) ethanol were obtained. The yield, specific rotation and optical purity determined by high-performance liquid chromatography were shown in Table 9.

Then, by epoxidation in the same way as Example 9 (-)-2'-methoxystyrene oxide, (-)-3'-methoxystyrene oxide and (-)-4'-methoxystyrene oxide were obtained. The yield and the specific rotation were as shown in Table 9.

                                      TABLE 9                                      __________________________________________________________________________     Substrate 2-chloro-1-                                                                              2-chloro-1-                                                                              2-chloro-1-                                                (2'-methoxy-                                                                             (3'-methoxy-                                                                             (4'-methoxy-                                               phenyl)ethanone                                                                          phenyl)ethanone                                                                          phenyl)ethanone                                  Reaction  (-)-2-chloro-1-                                                                          (-)-2-chloro-1-                                                                          (-)-2-chloro-1-                                  product   (2'-methoxy-                                                                             (3'-methoxy-                                                                             (4'-methoxy-                                               phenyl)ethanol                                                                           phenyl)ethanol                                                                           phenyl)ethanol                                   Yield     1.4 g     1.4 g     1.4 g                                            Form      Colorless oil                                                                            Colorless oil                                                                            Colorless oil                                    Boil. point                                                                              135° C./4 mmHg                                                                    140° C./4 mmHg                                                                    145° C./4 mmHg                            Specific  -68.25°                                                                           -34.74°                                                                           -41.50°                                   rotation                                                                       [α].sub.D.sup.20                                                         (C = 1, CH.sub.3 OH                                                            Op. purity                                                                               100% e.e. 100% e.e. --                                               H-NMR     3.00(br, S, 1H)                                                                          2.80(br, S, 1H)                                                                          2.82(br, S, 1H)                                  (90 MHz   3.40-4.00(m, 2H)                                                                         3.78(S, 3H)                                                                              3.36-3.90(m, 2H)                                 CDCl.sub.3)                                                                              3.83(S, 3H)                                                                              3.43-3.90(m, 2H)                                                                         3.78(S, 3H)                                      δ ppm                                                                              5.12(dd, J=5.5,                                                                          4.83(dd, J=4.5,                                                                          4.85(dd, J=5.5,                                            8.5Hz, 1H)                                                                               7.5Hz, 1H)                                                                               7.5Hz, 1H)                                                 6.74-7.56(m, 4H)                                                                         6.73-7.47(m, 4H)                                                                         6.93(d, J=9.0                                                                  Hz, 2H)                                                                        7.33(d, J=9.0,                                                                 Hz, 2H)                                          Reaction  (-)-2'-methoxy-                                                                          (-)-3'-methoxy-                                                                          (-)-4'-methoxy-                                  product   styrene oxide                                                                            styrene oxide                                                                            styrene oxide                                    Yield     0.7 g     0.7 g     0.7 g                                            Form      Colorless oil                                                                            Colorless oil                                                                            Colorless oil                                    Boil. point                                                                              110°  C./4 mmHg                                                                   115° C./4 mmHg                                                                    120° C./4 mmHg                            Specific  -58.95°                                                                           -14.95°                                                                           -23.00°                                   rotation                                                                       [α].sub.D.sup.20                                                         (C = 1, CH.sub.3 OH)                                                           H-NMR     2.68(dd, J=2.5,                                                                          2.73(dd, J=2.5,                                                                          2.75(dd, J=2.5,                                  (90 MHz   6.0Hz, 1H)                                                                               6.0Hz, 1H)                                                                               5.5Hz, 1H)                                       CDCl.sub.3)                                                                              3.12(dd, J=3.0,                                                                          3.05(dd, J=5.5,                                                                          3.04(dd, J=4.5,                                  δ ppm                                                                              6.0Hz, 1H)                                                                               6.0Hz, 1H)                                                                               5.5Hz, 1H)                                                 3.85(S, 3H)                                                                              3.75(S, 3H)                                                                              3.75(S, 3H)                                                4.20(dd, J=2.5,                                                                          3.56-3.92(m, 1H)                                                                         3.47-3.87(m, 1H)                                           3.0Hz, 1H)                                                                               6.61-7.40(m, 4H)                                                                         6.83(d, J=9.0,                                             6.76-7.43(m, 4H)    Hz, 2H)                                                                        7.16(d, J=9.0,                                                                 Hz, 2H)                                          __________________________________________________________________________

EXAMPLE 15

Cultivation, reaction and purification were carried out in the same way as described in Example 9 except that 2-chloro-1-(2',5'-dimethoxyphenyl) ethanone, 2-chloro-1-(3',4'-dimethoxyphenyl) ethanone were used as substrate and (-)-2-chloro-1-(2',5'-dimethoxyphenyl) ethanol, (-)-2-chloro-1-(3',4'-dimethoxyphenyl) ethanol were obtained. The yield, specific rotation and optical purity determined by high-performance liquid chromatography were shown in Table 10.

Then, by epoxidation of (-)-2-chloro-1-(2',5'-dimethoxyphenyl) ethanol in the same way as Example 9 (-)-2',5'-dimethoxystyrene oxide was obtained. The yield and the specific rotation were as shown in Table 10.

                                      TABLE 10                                     __________________________________________________________________________     Substrate 2-chloro-1-(2',5'-                                                                           2-chloro-1-(3',4'-                                               dimethylphenyl)ethanone                                                                      dimethylphenyl)ethanone                                Reaction  (-)-2-chloro-1-(2',5'-                                                                       (-)-2-chloro-1-(3',4'-                                 product   dimethoxypheny)ethanol                                                                       dimethoxypheny)ethanol                                 Yield     1.4 g         1.3 g                                                  Form      Colorless oil Colorless oil                                          Boil. point                                                                              150° C./4 mmHg                                                                        175° C./4 mmHg                                  Specific  -51.27°                                                                               -25.59°                                         rotation                                                                       [α].sub.D.sup.20                                                         (C = 1, CH.sub.3 OH)                                                           Optical   100% e.e.     100% e.e.                                              purity                                                                         H-NMR     3.16(br, S, 1H)                                                                              2.80(br, S, 1H)                                        (90 MHz   3.73(S, 3H)   3.85(S, 6H)                                            CDCl.sub.3)                                                                              3.77(S, 3H)   3.40-3.80(m, 2H)                                       δ ppm                                                                              3.40-3.93(m, 2H)                                                                             4.75(dd, J=6.0, 7.5Hz, 1H)                                       5.08(dd, J=4.0, 8.0Hz, 1H)                                                                   6.60-7.05(m, 3H)                                                 6.60-7.10(m, 3H)                                                     Reaction  (-)-2'-5°-dimethoxy-                                          product   styrene oxide                                                        Yield     0.7 g                                                                Form      Colorless oil                                                        Boil. point                                                                              140° C./4 mmHg                                                Specific  -33.47°                                                       rotation                                                                       [α].sub.D.sup.20                                                         (C = 1, CH.sub.3 OH)                                                           H-NMR     2.64(dd, J=2.5, 6.0Hz, 1H)                                           (90 MHz   3.08(dd, J=4.0, 6.0Hz, 1H)                                           CDCl.sub.3)                                                                              3.72(S, 3H)                                                          δ ppm                                                                              3.79(S, 3H)                                                                    4.15(dd, J=2.5, 4.0Hz, 1H)                                                     6.55-7.05(m, 3H)                                                     __________________________________________________________________________

EXAMPLE 16

Cultivation and reaction were carried out in the same way as described in Example 9 except that 2-chloro-1-(2',3',4'-trimethoxyphenyl) ethanone, 2-chloro-1-(3',4',5'-trimethoxyphenyl) ethanone were used as substrate and after completion of reaction, extraction was done twice using 300 ml of ethyl acetate. After dehydration of the ethyl acetate layer, the solvent was removed under reduced pressure, the resulting oily substance was refined by silica gel chromatography (hexane/ethyl acetate=7/1) and (-)-2-chloro-1-(2',3',4'-trimethoxyphenyl) ethanol, (-)-2-chloro-1-(3',4',5'-trimethoxyphenyl) ethanol were obtained. Their yield and specific rotation were as shown in Table 11.

                                      TABLE 11                                     __________________________________________________________________________     Substrate 2-chloro-1-(2',3',4'-                                                                        2-chloro-1-(3',4',5'-                                            trimethoxyphenyl)ethanone                                                                    trimethoxyphenyl)ethanone                              Reaction  (-)-2-chloro-1-(2',3',                                                                       (-)-2-chloro-1-(3',4',                                 product   4'-trimethoxyphenyl)ethanol                                                                  5'-trimethoxyphenyl)ethanol                            Yield     1.2 g         1.3 g                                                  Form      Colorless oil Crystal (mp. 65.5° C.)                          Specific  -22.05°                                                                               -24.76°                                         rotation                                                                       [α].sub.D.sup.20                                                         (C = 1, CH.sub.3 OH)                                                           Optical   --            --                                                     purity                                                                         H-NMR     2.89(br, S, 1H)                                                                              2.82(br, S, 1H)                                        (90 MHz   3.86(S, 6H)   3.36-3.76(m, 2H)                                       CDCl.sub.3)                                                                              3.96(S, 3H)   3.80 (S, 3H)                                           δ ppm                                                                              3.42-4.23(m, 2H)                                                                             3.84(S, 6H)                                                      5.08(dd, J=3.5, 7.5Hz, 1H)                                                                   4.80(dd, J=4.5, 7.5Hz, 1H)                                       6.71(d, j=9.0, Hz, 1H)                                                                       6.60(S, 1H)                                                      7.16(d, J=9.0, Hz, 1H)                                               __________________________________________________________________________

INDUSTRIAL APPLICATION POSSIBILITY

As shown in the examples, the present invention enables efficient manufacture of optically active (-)-2-halo-1-(substituted phenyl) ethanol and (-)-substituted styrene oxide. 

We claim:
 1. A method of preparing a (-)-2-halo-1-(substituted phenyl) ethanol of the formula ##STR5## wherein X is chlorine or bromine and each of R¹, R², R³ is hydrogen, chlorine, fluorine, methyl or methoxy, and wherein R¹, R² and R³ are not all hydrogen at the same time, and * indicates an asymmetric carbon atom,which comprises subjecting a 2-halo-1-(substituted phenyl) ethanone of the formula ##STR6## to the action of a microorganism selected from the group consisting of Ashbya gossypii IFO 0560, Brettanomyces custersianus IFO 1585, Candida intermedia IFO 0761, Candida krusei IFO 0011, Candida magnoliae IFO 0705, Candida pinus IFO 0741, Candida saitoana IFO 0768, Candida tropicalis IFO 1403, Cryptococcus albidus IFO 0378, Cryptococcus terreus IFO 0727, Trichosporon loubieri CBS 7065, Pichia farinosa IFO 0574, Pichia membranaefaciens IFO 0460, Rhodosporidium toruloides IFO 0871, Rhodotorula graminis IFO 0190, Rhodotorula minuta IFO 0387, Rhodotorula rubra IFO 0383, Saccharomyces cerevisiae IFO 0614 and Trigonopsis variabilis IFO 0671 and recovering said substituted phenyl ethanol. P 